Sudden elevation of plasma D-dimer levels induced by the combination therapy of dabrafenib and trametinib: Report of two cases.

The combination therapy of dabrafenib and trametinib revolutionized the treatment for BRAF V600-mutated melanoma. Various adverse events have been reported for this treatment, most notably fever. Herein, we report two cases of novel an adverse event, namely sudden and significant elevation of plasma D-dimer level induced by this therapy. In the first case, the remarkable elevation of plasma D-dimer level up to 87.4 mg/dL was noted on day 11, and in the second case, the plasma D-dimer level reached 125.5 mg/dL on day 25. In both cases, D-dimer levels gradually decreased after the cessation of this therapy. Although the exact cause is not clear, we assume two possible hypotheses: the first is that the combination therapy may induce disseminated intravascular coagulation, and the second is that the therapy induced pathological condition of secondary thrombotic microangiopathies. Our cases suggest that this thrombotic adverse event should not be overlooked, and coagulation parameters need to be monitored during the course of this treatment.

Approach for the Derivation of Melanocytes from Induced Pluripotent Stem Cells.

Induced pluripotent stem (iPS) cells have the ability to differentiate into multiple cell types in the body and have an unlimited growth potential. However, iPS cell-derived melanocytes produced by existing protocols have significant limitations in developing novel strategies for regenerative medicine and cell therapies of pigmentation disorders in humans because they involve culture in media containing fetal bovine serum and nonphysiological agents. In this study, we established an in vitro approach to generate iPS cell-derived human melanocytes that have higher proliferation rates and increased melanin production compared with melanocytes prepared by previously reported approaches. Importantly, our iPS cell-derived human melanocytes are prepared in fetal bovine serum-free culture conditions that do not contain any nonphysiological agents. We designed two original methods, transferring black colonies by pipette and recovering black cell pellets from centrifuged medium, and numerous human iPS cell-derived melanocytes proliferated in gelatinous dishes coated with Matrigel after 12 days. We also succeeded in inducing melanin pigmentation in the nude mouse skin in vivo using those human iPS cell-derived melanocytes. We propose that this method using iPS cells established from T cells in the blood of normal human volunteers could be applied clinically to develop regenerative medicine and cell therapies for various forms of human pigmentation disorders.

Serum peptides as putative modulators of inflammation in psoriasis.

BACKGROUND: Psoriasis is a refractory inflammatory disease, however, its pathophysiology is still not fully understood. OBJECTIVE: We tried to identify novel serum peptides associated with the pathophysiology of psoriasis. METHODS: Serum peptides from 24 patients with psoriasis vulgaris (PV), 10 patients with psoriatic arthritis (PsA), 14 patients with atopic dermatitis (AD), and 23 healthy control (HC) subjects were analyzed by mass spectrometry. The effects of some peptides on the secretion of humoral factors from dermal cells were investigated by cytokine arrays and ELISAs. RESULTS: A total of 93 peptides were detected. 24, 20, 23, and 2 peptides showed at least 1.2-fold difference in ion intensity between the psoriasis (PV+PsA) and HC groups, between the PV+PsA and AD groups, between the PV and PsA groups, and between patients with severe-to-moderate PV (n=6) and those with mild PV (n=18), respectively (p<0.05). 13 out of 27 peptides that showed at least 1.5-fold ion intensity difference in the abovementioned 4 comparisons were identified. The parent proteins of the identified peptides included a coagulation factor, proteins involved in the maintenance of skin, and a protein relating to cytoskeleton. We focused on 2 peptides that were increased in the PV+PsA group: a fibrinogen α chain-derived peptide (1462m/z), the unmodified form of which was fibrinopeptide A-des-alanine (FPAdA), and a filaggrin (FLG)-derived peptide (1977m/z), a modified form of FLG2099-2118 (Q2099pE, Q2115E; FLG-pEE). FPAdA stimulation increased the secretion of GROα from dermal microvascular endothelial cells (dMVECs) and decreased the secretion of lipocalin-2 from keratinocytes in comparison to FPAdA-resequenced peptide stimulation (GROα, 280.9±7.3pg/mL vs. 229.6±5.0pg/mL, p<0.001; lipocalin-2, 273±13pg/mL vs. 350±10pg/mL, p<0.01). Interestingly, FLG-pEE stimulation decreased the secretion of GROα, IL-8, and MCP-1 from dMVECs in comparison to FLG-derived control peptide stimulation (GROα, 844.3±47.5pg/mL vs. 1038.5±96.9pg/mL, p<0.05; IL-8, 2240.1±172.6pg/mL vs. 3221.8±523.7pg/mL, p<0.05; MCP-1, 4057.8±157.2pg/mL vs. 4619.1±213.4pg/mL, p<0.05). CONCLUSIONS: The results suggested that some serum peptides are involved in the pathophysiology of psoriasis, regulating the secretion of inflammatory chemokines and an antimicrobial protein. The modulation of serum peptides may be a potential therapeutic strategy for psoriasis.

Presence of anti-phosphatidylserine-prothrombin complex antibodies and anti-moesin antibodies in patients with polyarteritis nodosa.

We measured both serum anti-phosphatidylserine-prothrombin complex (anti-PSPT) antibodies and anti-moesin antibodies, as well as various cytokines (interleukin [IL]-2, IL-4, IL-5, IL-10, IL-13, IL-17, granulocyte macrophage colony-stimulating factor, γ-interferon, tumor necrosis factor-α) levels in polyarteritis nodosa (PAN) patients with cutaneous manifestations. All patients showed the presence of a histological necrotizing vasculitis in the skin specimen. They were treated with i.v. cyclophosphamide pulse therapy (IV-CY) and prednisolone therapy or steroid pulse therapy. The immunological assessments were performed on sera collected prior to and after treatment with IV-CY or steroid pulse therapy. We found a significant positive correlation between serum anti-moesin antibodies and both clinical Birmingham Vasculitis Activity Scores and Vasculitis Damage Index. Anti-PSPT antibody and IL-2 levels after treatment in PAN patients were significantly lower than before treatment. In contrast, anti-moesin antibody levels were higher following IV-CY or steroid pulse therapy compared with the pretreatment levels. In the treatment-resistant PAN patients (n = 8), anti-PSPT antibody levels after treatment were significantly lower than before treatment. In contrast, anti-moesin antibody levels after treatment in the patients were significantly higher compared with the pretreatment levels. Immunohistochemical staining revealed moesin overexpression in mainly fibrinoid necrosis of the affected arteries in the PAN patients. We suggest that measurement of serum anti-PSPT antibody levels could serve as a marker for PAN and aid in earlier diagnosis of PAN. We also propose that elevated serum anti-moesin antibodies could play some role of the exacerbation in patients with PAN.

Relationship among antineutrophil cytoplasmic antibody, blood urea nitrogen and complement in patients with eosinophilic granulomatosis polyangiitis (Churg-Strauss syndrome).

Eosinophilic granulomatosis with polyangiitis (EGPA), also known as Churg-Strauss syndrome, is an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis characterized by a history of asthma, hypereosinophilia. The prevalence of ANCA in EGPA is less common than in other ANCA-associated vasculitis. Increasing evidence of complement activation in the pathogenesis of ANCA-associated vasculitis has been provided by studies in animal models. We examined EGPA patients with cutaneous manifestations as an initial sign and investigated the correlations among clinical, serological and histopathological findings. We focused on differences among ANCA, blood urea nitrogen and complement levels such as complement 3 (C3), C4 and total complement hemolytic activity (CH50). We retrospectively investigated the records of 22 patients (11 male and 11 female) with EGPA admitted to our hospital from 1997-2012. Ten of the 22 patients (46%) were positive for serum myeloperoxidase (MPO)-ANCA. In contrast, all the patients were negative for serum proteinase 3 ANCA. There was a significantly positive correlation between serum CH50 and C4 levels in patients with EGPA. Serum blood urea nitrogen (BUN) levels differed significantly between MPO-ANCA-positive and -negative patients. Serum CH50 levels were higher in MPO-ANCA-positive patients compared to negative patients. Serum BUN levels were higher in elevated CH50 patients compared to normal and low CH50-negative patients. We propose that positive findings for MPO-ANCA with CH50 high activity may be a risk factor for developing renal insufficiency. Assuming there are correlations between the presence of ANCA and complements, earlier diagnosis based on initial efficacious treatment for EGPA.

Prevalence of dermatological disorders in Japan: a nationwide, cross-sectional, seasonal, multicenter, hospital-based study.

To clarify the prevalence of skin disorders among dermatology patients in Japan, a nationwide, cross-sectional, seasonal, multicenter study was conducted in 69 university hospitals, 45 district-based pivotal hospitals, and 56 private clinics (170 clinics in total). In each clinic, information was collected on the diagnosis, age, and gender of all outpatients and inpatients who visited the clinic on any one day of the second week in each of May, August, and November 2007 and February 2008. Among 67,448 cases, the top twenty skin disorders were, in descending order of incidence, miscellaneous eczema, atopic dermatitis, tinea pedis, urticaria/angioedema, tinea unguium, viral warts, psoriasis, contact dermatitis, acne, seborrheic dermatitis, hand eczema, miscellaneous benign skin tumors, alopecia areata, herpes zoster/postherpetic neuralgia, skin ulcers (nondiabetic), prurigo, epidermal cysts, vitiligo vulgaris, seborrheic keratosis, and drug eruption/toxicoderma. Atopic dermatitis, impetigo, molluscum, warts, acne, and miscellaneous eczema shared their top-ranking position in the pediatric population, whereas the most common disorders among the geriatric population were tinea pedis, tinea unguium, psoriasis, seborrheic dermatitis, and miscellaneous eczema. For some disorders, such as atopic dermatitis, contact dermatitis, urticaria/angioedema, prurigo, insect bites, and tinea pedis, the number of patients correlated with the average high and low monthly temperatures. Males showed a greater susceptibility to some diseases (psoriasis, erythroderma, diabetic dermatoses, inter alia), whereas females were more susceptible to others (erythema nodosum, collagen diseases, livedo reticularis/racemosa, hand eczema, inter alia). In conclusion, this hospital-based study highlights the present situation regarding dermatological patients in the early 21st century in Japan.

IgM in lesional skin of adults with Henoch-Schönlein purpura is an indication of renal involvement.

BACKGROUND: Henoch-Schönlein purpura (HSP) is a multisystem disease believed to be a consequence of the entrapment of circulating IgA-containing immune complexes in blood vessel walls throughout the skin, kidneys, and gastrointestinal tract. The skin manifestations are characterized by nonthrombocytopenic palpable purpura over the lower extremities. OBJECTIVE: We assessed adult patients with HSP who had nonthrombocytopenic palpable purpura on the extensor surfaces of their lower limbs, and had no associated connective tissue disease. Patient medical records, including clinical presentation, laboratory data, and direct immunofluorescence (DIF) reports, were reviewed retrospectively. METHODS: We reviewed the records of 25 adult patients with HSP who presented at our department, between 2006 and 2008, with an initial cutaneous manifestation of palpable purpura on their lower extremities. Adult HSP was defined in all cases as documented leukocytoclastic vasculitis according to a skin biopsy specimen, with histopathologic evidence of IgA deposition by DIF. Statistical analyses were performed using a χ(2) test to compare prevalence among each clinical manifestation. RESULTS: There was a significant correlation between IgM deposition by DIF and renal involvement (χ(2) = 5.23, P = .022). IgM deposition and complement 3 deposition by DIF showed a close relationship (χ(2) = 5.11, P = .024). There was a significant positive correlation between serum IgA and C-reactive protein levels (Spearman's rank correlation coefficient = 0.35, P = .044). LIMITATIONS: These findings should be validated in larger studies. Renal biopsies were not done to confirm the presence of nephritis. CONCLUSIONS: This study suggests that IgM deposition in palpable purpura based on DIF provides an indicator of nephritis in adult patients with HSP. We believe that IgM deposition could be related to the pathogenic factors that trigger the development of renal involvement.